Since about 1950 a number of medical devices which make contact with the blood of living persons have been developed, manufactured, and used clinically. A partial list would include the pacemaker, arterial graft, prosthetic heart valve, artificial heart, hip prosthesis, heart lung machine, and kidney dialysis machine. The growing artificial organ market in the United States serves several hundred thousand patients at present, and amounts to several billions of dollars annually.
A major problem with artificial organs is that their surfaces are foreign to the blood and tend to initiate red cell destruction, denaturation of proteins, and the coagulation of blood to form clots (thrombogenesis). Of these, the problem of thrombus formation is probably the most severe because of the lethal nature of a suddenly curtailed blood supply to vital organs.
Little was known about the mechanism of blood coagulation until 1905, when P. Morawitz proposed a scheme that remained virtually unchanged until the 1930's. Essentially his concept was the following:
I. prothrombin+activating factors.fwdarw.thrombin PA1 II. fibrinogen+thrombin.fwdarw.fibrin
The conversion of one of the blood proteins, fibrinogen, into a jelly-like solid polymer, fibrin, is one of the major processes in thrombus formation. Later research showed that blood coagulation is a process of great complexity, involving a "coagulation cascade" of reactions which progressively activate a sequence of enzymes known as "factors".
The blood platelets (thrombocytes) also play an important role in thrombus formation, after first being activated by contact with a foreign substance such as plastic. Each activated platelet tends to adhere to the plastic surface and to adjacent platelets forming aggregates. Such clumps or aggregates of platelets, with interwoven strands of fibrin polymer, make up the bulk of the thrombus or clot.
A number of treatments have been devised to render plastics thromboresistant (resistant to clotting), and many promising materials have been developed. However, none of these materials has been completely satisfactory for use in such applications as the artificial heart, kidney, or lung. Such applications would not be possible at present without the use of systemic anticoagulants such as heparin, warfarin, and various antiplatelet agents. At the same time, systemic anticoagulation is not a satisfactory answer because of control problems and the danger of hemorrhage. The administration of any type of anticoagulant into the patient's blood is of short-term effectiveness because the anticoagulant is dissipated by the body.
Blood-contact plastics coated with heparin-containing formulations have been tried, but such coatings are washed away by the blood. Heparin ionically bound to a plastic surface is not permanent, but is eventually removed by the blood flow. Covalently bound heparin has the advantage of permanence, but any type of heparinized surface may lead to thrombocytopenia (J. C. Nelson, Arch. Intern. Med., 138, 548 (1978)), and evidence has been found that heparin induces arterial embolism (R. A. Baird, J. Bone Jt. Surg. Am., 59A, 1061 (1977)). Surface-bound heparin on blood-contact prosthetic devices has been observed to cause a profound shortening of platelet survival time (G. L. Schmer, Trans. Am. Soc. Artif. Intern. Organs, 22, 654 (1976)).